While heart attack and stroke now cause fewer deaths than previously, deaths due to heart failure (inability of the heart to deliver adequate blood supply to vital organs via the systemic circulation) have increased markedly (82.5%) between 1979 and 1992. In 1997, heart failure is expected to cause at least 250,000 deaths in the United States. More than 400,000 new cases of heart failure are expected to be diagnosed in 1997. In all, it is estimated that more than 4 million Americans are presently living with this dangerous condition.
Sixty to seventy percent of these cases of heart failure are due to ischemic causes, i.e., insufficient delivery of blood flow and vital oxygen via the coronary circulation to the cardiac muscle. This can be due to mechanical obstruction of the coronary arteries, for example by atherosclerotic deposits, to spasm (temporary occlusion) of the coronary arteries, or to restenosis of coronary arteries that have been previously opened by angioplasty (balloon catheter dilation).
Certain segments of the general population are particularly prone to heart failure. Heart attack survivors have a four to six times greater risk of having an additional heart attack. Patients with angina (ischemic coronary pain), diabetes mellitus, or uncontrolled high blood pressure have a two-fold risk of developing heart failure compared to the general population.
Current treatments of heart failure include agents which dilate, and thus, relax blood vessels reducing arterial resistance against which the heart must work. Converting enzyme inhibitors such as captopril, enalpril and lisinopril are examples of such arterial vasodilators. Side effects such as rash, persistent cough, excessive lowering of blood pressure and adverse effects on kidney function limit the use of these agents in therapy. Other drugs which work by directly dilating blood vessels (arteries), such as hydralazine, prazocin and doxazocin also reduce the resistance against which the failing heart must pump, but these drugs too can cause excessive lowering of blood pressure, as well as reflex tachycardia (increased heart rate) which increases cardiac work and oxygen demand by the heart muscle already deprived of an adequate oxygen supply in the case of ischemic heart failure.
Because of their positive inotropic effect, cardiac glycosides (e.g., digitalis, ouabain) have been considered unrivaled in value for the treatment of heart failure. Positive inotropic effect generally refers to the enhancement of the contractility of the cardiac cells in a dose-dependent manner. Cardiac glycosides are most frequently used therapeutically to increase the adequacy of the circulation in patients with congestive heart failure and to slow the ventricular rate in the presence of atrial fibrillation.
However, cardiac glycosides have narrow therapeutic indices and their use is frequently accompanied by toxic effects that can be severe or lethal. The most important toxic effects, in terms of risk to the patient, are those that involve the heart (e.g., abnormalities of cardiac rhythm and disturbances of atrio-ventricular conduction). Gastrointestinal disorders, neurological effects, anorexia, blurred vision, nausea and vomiting are other common cardiac glycoside-induced reactions.
In the case of ischemic heart disease, other classes of compounds have been used to improve blood flow to the failing myocardium through dilation of the coronary arteries. Examples of these agents include nitrates, such as isosorbide dinitrate, and calcium channel blockers such as diltiazem, nifedipine and verapamil.
Nitrates and calcium channel blockers do not have direct effects on the contractile mechanism of the cardiac muscle cells. That is, they are not positive inotropic agents. Digitalis and ouabain, on the other hand, are strong inotropes, but do not have vasoactive (dilatory) effects on the coronary circulation. Hypothalamic inhibitory factor (HIF) has also been shown to produce a positive inotropic effect on cardiac muscle cells (U.S. patent application Ser. No. 08/338,264, filed Nov. 10, 1994). However, HIF was not shown to have vasoactive (dilatory) effects on the coronary circulation.
A single compound which has both inotropic effects and coronary vasodilatory effects would be highly desirable as an agent to treat ischemic heart failure since both abnormalities are present and each contributes to the morbidity of the condition. To this point, such a compound has not been identified or made available pharmaceutically for the treatment of ischemic heart failure.